U.S. patent application number 17/506051 was filed with the patent office on 2022-02-17 for medical device for delivery of lifting agent.
The applicant listed for this patent is Boston Scientific Scimed, Inc.. Invention is credited to Matthew B. Hollyer, Samuel Raybin.
Application Number | 20220047807 17/506051 |
Document ID | / |
Family ID | 1000005940252 |
Filed Date | 2022-02-17 |
United States Patent
Application |
20220047807 |
Kind Code |
A1 |
Raybin; Samuel ; et
al. |
February 17, 2022 |
Medical Device for Delivery of Lifting Agent
Abstract
A medical device comprising a syringe barrel, a plunger, and an
injectable viscous lifting agent containing a coloring agent loaded
in the syringe barrel. The injectable viscous lifting agent is
sterilized by a sterilization process, such as an autoclaving
process, while inside the syringe barrel. The injectable viscous
lifting agent is adapted for injection between an upper mucosal
layer and a lower layer at a target treatment site such that the
upper mucosal layer separates from the lower layer and the upper
mucosal layer is elevated.
Inventors: |
Raybin; Samuel; (San Jose,
CA) ; Hollyer; Matthew B.; (Watertown, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boston Scientific Scimed, Inc. |
Maple Grove |
MN |
US |
|
|
Family ID: |
1000005940252 |
Appl. No.: |
17/506051 |
Filed: |
October 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15469797 |
Mar 27, 2017 |
|
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17506051 |
|
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62316891 |
Apr 1, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
47/36 20130101; A61M 5/178 20130101; A61L 31/14 20130101; A61M
5/158 20130101; A61J 1/10 20130101; A61K 9/0024 20130101; A61M
2205/36 20130101; A61L 31/042 20130101 |
International
Class: |
A61M 5/158 20060101
A61M005/158; A61K 9/06 20060101 A61K009/06; A61K 47/36 20060101
A61K047/36; A61K 9/00 20060101 A61K009/00; A61J 1/10 20060101
A61J001/10; A61L 31/04 20060101 A61L031/04; A61L 31/14 20060101
A61L031/14; A61M 5/178 20060101 A61M005/178 |
Claims
1. A medical device comprising a syringe barrel, a plunger, and an
injectable viscous lifting agent loaded in the syringe barrel,
wherein the injectable viscous lifting agent comprises a coloring
agent, wherein the injectable viscous lifting agent has been
sterilized by a sterilization process while inside the syringe
barrel.
2. The medical device of claim 1, wherein the injectable viscous
lifting agent is adapted for injection between an upper mucosal
layer and a lower layer at a target treatment site such that the
upper mucosal layer separates from the lower layer, elevating the
upper mucosal layer.
3. The medical device of claim 1, wherein the sterilization process
is autoclaving.
4. The medical device of claim 1, wherein the injectable viscous
lifting agent is transparent blue in appearance.
5. The medical device of claim 1, wherein the medical device
further comprises a needle through which the injectable viscous
lifting agent is injected.
6. The medical device of claim 5, wherein the needle is a 23 gauge
needle.
7. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises a polysaccharide gelling agent.
8. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises an anionic gelling agent.
9. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises a neutral gelling agent.
10. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises a natural gum.
11. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises a vegetable gum or a microbial gum.
12. The medical device of claim 1, wherein the injectable viscous
lifting agent comprises gellan gum.
13. Use of the medical device of claim 1 as a submucosal lifting
agent.
14. A method of separating and elevating an upper mucosal layer
from a lower layer using the medical device of claim 5, the method
comprising injecting the injectable viscous lifting agent through
the needle into a target treatment site between the upper mucosal
layer and the lower layer.
15. The method of claim 14, wherein the method is performed as part
of an endoscopic mucosal resection procedure or an endoscopic
submucosal dissection procedure.
16. The method of claim 15, wherein the medical device further
comprises a flexible tube that couples the syringe barrel to the
needle and wherein the injectable viscous lifting agent is injected
from the syringe barrel, through the flexible tube, through the
needle and into the target site.
17. A finished medical device comprising a single-barrel syringe
pre-loaded with an injectable viscous lifting agent dyed with a
coloring agent.
18. The medical device of claim 17, wherein the medical device
further comprises a needle through which the injectable viscous
lifting agent is injected.
19. The medical device of claim 17, wherein the injectable viscous
lifting agent comprises a polysaccharide gelling agent.
20. The medical device of claim 17, wherein the injectable viscous
lifting agent comprises an anionic gelling agent.
21. The medical device of claim 17, wherein the injectable viscous
lifting agent comprises a natural gum.
22. A medical device comprising a pre-loaded, sterilized syringe,
wherein the syringe has been pre-loaded with an injectable viscous
lifting agent and a coloring agent prior to the syringe being
sterilized.
23. The medical device of claim 22, wherein the medical device
further comprises a needle through which the injectable viscous
lifting agent is injected.
24. The medical device of claim 22, wherein the injectable viscous
lifting agent comprises a polysaccharide gelling agent.
25. The medical device of claim 22, wherein the injectable viscous
lifting agent comprises an anionic gelling agent.
26. The medical device of claim 22, wherein the injectable viscous
lifting agent comprises a natural gum.
27. A medical device comprising an injectable viscous lifting agent
and a coloring agent loaded in a syringe barrel, wherein the
injectable viscous lifting agent is dyed with the coloring agent
while inside the syringe barrel.
28. The medical device of claim 27, wherein the injectable viscous
lifting agent comprises a polysaccharide gelling agent.
29. The medical device of claim 27, wherein the injectable viscous
lifting agent comprises an anionic gelling agent.
30. The medical device of claim 27, wherein the injectable viscous
lifting agent comprises a natural gum.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of Ser. No. 15/469,797, filed Mar.
27, 2017, which claims the benefit of priority under 35 U.S.C.
.sctn. 119 to U.S. Provisional Application No. 62/316,891, filed on
Apr. 1, 2016, the disclosures of which are incorporated by
reference in their entirety for all purposes.
TECHNICAL FIELD
[0002] Embodiments of the present disclosure relate generally to
compositions suitable for injection, methods of preparation
thereof, and devices comprising such compositions.
BACKGROUND
[0003] Various medical procedures are used for diagnosis and/or
treatment of tissue. For example, an endoscopic procedure may be
performed to take tissue samples from the gastrointestinal (GI)
tract or other organ systems for pathological evaluation and/or
therapeutic purposes, such as detection and removal of
pre-cancerous mucosal tissue or tumors. Yet, removing select
portions of tissue from a patient with minimal disturbance to
underlying anatomy can be challenging.
[0004] In medical procedures such as endoscopic mucosal resection
(EMR) and endoscopic submucosal dissection (ESD), a fluid may be
injected into tissue to separate different tissue layers to assist
in the removal of lesions. For example, a fluid may be injected to
separate submucosal tissue from mucosal tissue. The injected fluid
generally elevates the target tissue from underlying tissue layers
to allow a physician to more easily resect the target tissue. Yet,
fluids used for this purpose, such as saline, tend to dissipate
within a few minutes, and can require periodic re-injection to
ensure the target tissue remains raised throughout the procedure.
More viscous injection solutions have been identified, but these
alternatives are often costly, difficult to inject, and/or also
prone to dissipation/breaking down too soon after injection.
SUMMARY OF THE DISCLOSURE
[0005] The present disclosure includes compositions useful for
tissue resection procedures and methods of preparing such
compositions. According to some aspects of the present disclosure,
the composition may comprise a gel formed from a polysaccharide
such as gellan gum, water, and a salt as a source of monovalent or
divalent cations. The gel may be allowed to set undisturbed, e.g.,
in a reservoir, to form a continuous, three-dimensional network
prior to injection from the reservoir to a patient. The continuous,
three-dimensional network may provide for a homogeneous structure
of the gel.
[0006] The present disclosure includes, for example, a method of
preparing a composition for delivery to a target site of a patient,
wherein the method comprises combining gellan gum, at least one
salt, and water to form a mixture; heating the mixture; introducing
the mixture into a reservoir; and allowing the mixture to cool
while inside the reservoir to form a gel having a continuous,
three-dimensional structure inside the reservoir; wherein the
composition is biocompatible and injectable from the reservoir
through a needle to the target site. According to some aspects, the
composition comprises 0.01% to 2.0% gellan gum by weight with
respect to the total weight of the composition, or 0.05% to 0.5%
gellan gum by weight with respect to the total weight of the
composition. In some aspects, the composition may comprise one or
more additional agents, such as a coloring agent.
[0007] The mixture may be introduced into the reservoir after
heating the mixture at a temperature ranging from about 70.degree.
C. to about 130.degree. C. According to some aspects, the
temperature of the mixture when being introduced into the reservoir
may range from about 70.degree. C. to about 130.degree. C.
According to some aspects, the mixture may be allowed to cool
before introducing the mixture into the reservoir. For example,
after allowing the mixture to cool and introducing the mixture into
the reservoir, the mixture may be heated at a temperature ranging
from about 70.degree. C. to about 130.degree. C. while inside the
reservoir. In some examples, heating the mixture may sterilize the
mixture, such that the gel formed inside the reservoir is
sterilized. For example, the mixture may be heated at or to a
temperature of about 121.degree. C. while inside the reservoir.
[0008] The reservoir may be a component of a medical device or
system. According to some aspects, for example, the reservoir may
be a barrel of a syringe, or may comprise a flexible pouch. In some
aspects, the reservoir may be coupled to a needle via a flexible
tube. The gel may form a continuous, three-dimensional network
across an entire cross-sectional dimension of the reservoir. For
example, if the reservoir comprises a cylindrical barrel of a
syringe, the continuous, three-dimensional structure of the gel may
extend across an entire diameter of the reservoir. The present
disclosure is not limited to cylindrical-shaped reservoirs,
however, and other cross-sectional shapes are contemplated and
encompassed herein.
[0009] According to some aspects, the method may be used to prepare
a medical device. For example, the present disclosure includes a
medical device prepared according to any of the aspects of the
methods discussed herein. Such a medical device may comprise, for
example, the reservoir containing the composition and a needle
through which the composition may be injected. Optionally, the
medical device may comprise a flexible tube connecting the
reservoir to the needle. In some aspects, the medical device may
comprise a syringe, such that the reservoir is provided by a barrel
of the syringe, or the reservoir may be provided by a flexible
pouch. The composition may be biocompatible. For example, the
composition may comply with governmental regulations for
pharmaceutical compositions and/or governmental regulations for
medical devices. According to some aspects, the composition and/or
the medical device comprising the composition may have an endotoxin
level of 20 endotoxin units (EU) or less, e.g., 15 EU or less, 10
EU or less, or 5 EU or less.
[0010] In some aspects, the present disclosure includes a medical
device comprising a needle; a reservoir coupled to the needle; and
a composition comprising 0.01% to 2.0% gellan gum by weight with
respect to a total weight of the composition; at least one salt;
and water. The composition of the medical device may be prepared by
combining the gellan gum, the at least one salt, and the water to
form a mixture; heating the mixture; introducing the mixture into
the reservoir; and allowing the mixture to cool and increase in
viscosity while inside the reservoir to form a homogeneous gel;
wherein the composition is injectable through the needle. The
medical device may be configured such that composition is
injectable from the reservoir through the needle to a target site
of a patient. According to some aspects, for example, the
composition may be allowed to set into a gel while inside the
reservoir to form a continuous, three-dimensional network, and may
not be transferred outside the reservoir prior to injection through
the needle. The continuous, three-dimensional structure of the gel
may extend across an entire cross-sectional dimension of the
reservoir.
[0011] According to some aspects, the composition of the medical
device may comprise 0.01% to 2.0% gellan gum by weight or 0.05% to
0.5% gellan gum by weight with respect to the total weight of the
composition. Further, for example, the at least one salt of the
composition may comprise one or more cations such as sodium,
calcium, and/or magnesium cations. In some examples, the
composition may comprise at least one sodium salt, at least one
calcium salt, at least one magnesium salt, or a combination
thereof. Additional salts providing for biocompatible compositions
are also contemplated. The composition may additionally or
alternatively comprise at least one coloring agent. In some
examples, the medical device may comprise a syringe, e.g., the gel
forming a continuous, three-dimensional network across an entire
cross-sectional dimension of the barrel of the syringe. In some
examples, the reservoir of the medical device may be coupled to the
needle via a flexible tube, or the reservoir may be directly
attached to the needle.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate various
exemplary aspects of the disclosure, and together with the
description serve to explain the principles of the present
disclosure.
[0013] FIGS. 1A-1C show exemplary medical devices in accordance
with certain aspects of the present disclosure.
[0014] FIGS. 2A-2E illustrate an exemplary tissue resection
procedure in accordance with certain aspects of the present
disclosure.
DETAILED DESCRIPTION
[0015] Particular aspects of the present disclosure are described
in greater detail below. The terms and definitions provided herein
control, if in conflict with terms and/or definitions incorporated
by reference.
[0016] As used herein, the terms "comprises," "comprising," or any
other variation thereof are intended to cover a non-exclusive
inclusion, such that a process, method, composition, article, or
apparatus that comprises a list of elements does not include only
those elements, but may include other elements not expressly listed
or inherent to such process, method, composition, article, or
apparatus. The term "exemplary" is used in the sense of "example"
rather than "ideal."
[0017] As used herein, the singular forms "a," "an," and "the"
include plural reference unless the context dictates otherwise. The
terms "approximately" and "about" refer to being nearly the same as
a referenced number or value. As used herein, the terms
"approximately" and "about" should be understood to encompass
.+-.5% of a specified amount or value.
[0018] The present disclosure includes compositions comprising at
least one gelling agent, at least one salt, and water. The
composition may be formulated as a biocompatible gel suitable for
injection.
[0019] The at least one gelling agent may be natural (including
natural gums such as vegetable gums and/or microbial gums) or
synthetic in origin, and may be anionic, cationic, or neutral.
Non-limiting examples of gelling agents suitable for the
compositions herein include polysaccharides such as gellan gum,
xanthan gum, gum arabic, guar gum, locust bean gum, alginate, and
carrageenans.
[0020] In some embodiments the composition may comprise gellan gum,
xanthan gum, or a mixture thereof. Gellan gum is a polysaccharide
produced by Sphingomonas bacteria, and has a general structure
formed of repeating units of four sugars linked together: two
residues of D-glucose, one residue of L-rhamnose, and one residue
of D-glucuronic acid. Xanthan gum is a polysaccharide produced by
Xanthomonas bacteria, and has a general structure formed of
repeating units of five sugars linked together: two residues of
D-glucose, two residues of D-mannose, and one residue of
D-glucuronic acid.
[0021] There are two types of gellan gum: native and deacylated.
The structure of native gellan gum includes two acyl groups,
acetate and glycerate, bound to the glucose residue adjacent to the
glucuronic acid residue. These acyl groups may be removed under
alkaline conditions to produce deacylated gellan gum, which results
in different stability and plasticity properties in comparison to
native gellan gum. For example, native gellan gum generally forms
softer, more elastic gels with thermoreversibility, whereas
deacylated gellan gum generally forms harder, more inelastic gels
with higher heat resistance. The compositions herein may comprise
native gellan gum, deacylated gellan gum, or a mixture thereof. In
at least one embodiment, the composition comprises deacylated
gellan gum.
[0022] Certain microbial extracts may comprise endotoxins, e.g.,
lipopolysaccharides from the bacteria that become combined with the
polysaccharide structure. In some embodiments, the gelling agent
may be chosen to minimize or eliminate the introduction of
endotoxins into the composition, or may be processed to reduce or
eliminate the concentration of endotoxins prior to use in the
compositions disclosed herein.
[0023] According to some aspects of the present disclosure, the
composition may comprise a microbial-sourced polysaccharide, e.g.,
xanthan gum, that has been processed to reduce the amount of
endotoxins present, such that the resulting composition is
pharmaceutically-acceptable and in compliance with the applicable
government regulatory standards. For example, the at least one
gelling agent may have an endotoxin level of 20 endotoxin units
(EU) or less, such as from 0 EU to 20 EU, from 0 EU to 10 EU, from
0 EU to 5 EU, from 1 EU to 20 EU, from 1 EU to 10 EU, or from 1 EU
to 5 EU. Thus, for example, a composition may have an endotoxin
level of 20 EU or less, such as from 0 EU to 20 EU, from 0 EU to 10
EU, from 0 EU to 5 EU, from 1 EU to 20 EU, from 1 EU to 10 EU, or
from 1 EU to 5 EU. In use, the composition may be delivered to a
target site of a patient via a suitable medical device (e.g., a
syringe or a fluid reservoir coupled to an injection needle). Thus,
for example, the medical device may have an endotoxin level of 20
EU or less, such as from 0 EU to 20 EU, from 0 EU to 10 EU, from 0
EU to 5 EU, from 1 EU to 20 EU, from 1 EU to 10 EU, or from 1 EU to
5 EU. Bacterial endotoxin levels may be measured, for example,
using the Limulus Amebocyte Lysate (LAL) test.
[0024] The concentration of gelling agent(s) may range from about
0.01% to about 2.0% by weight with respect to the total weight of
the composition, such as from about 0.02% to about 1.5%, from about
0.05% to about 0.5%, from about 0.10% to about 1.0%, from about
0.10% to about 0.30%, or from about 0.02% to about 0.25% by weight
with respect to the total weight of the composition, e.g., about
0.10%, about 0.15%, or about 0.20% by weight with respect to the
total weight of the composition. In at least one embodiment, the
total concentration of gelling agent(s) in the composition ranges
from about 0.05% to about 0.5% by weight with respect to the total
weight of the composition.
[0025] The at least one gelling agent may be combined with one or
more biocompatible, e.g., physiologically compatible, salts.
Non-limiting examples of salts suitable for the compositions herein
include salts comprising sodium, calcium, magnesium, and/or
potassium cations. The salts may include, for example, chloride
salts, phosphate salts, and/or sulfate salts, such as, e.g., sodium
chloride (NaCl), potassium chloride (KCl), calcium chloride
(CaCl.sub.2)), sodium dihydrogen phosphate (NaH.sub.2PO.sub.4),
potassium hydrogen phosphate (K.sub.2HPO.sub.4), magnesium sulfate
(MgSO.sub.4), sodium gluconate (C.sub.6H.sub.11NaO.sub.7), sodium
acetate trihydrate (C.sub.2H.sub.9NaO.sub.5.3H.sub.2O), and
magnesium chloride (MgCl.sub.2). For example, the at least one
gelling agent may comprise an anionic polysaccharide, and the
salt(s) may provide a source of monovalent or divalent cations
compatible with the polysaccharide.
[0026] In some embodiments, the composition may comprise a
physiologically compatible saline solution, such as, e.g., a sodium
chloride solution. For example, the composition may comprise a 0.9%
wt. sodium chloride solution, e.g., providing sodium cations to
assist in formation of the three-dimensional solid gel network. In
some embodiments, the composition may be isotonic. For example, the
saline solution may have an appropriate concentration of monovalent
and/or divalent cations such that the composition is isotonic with
tissue fluids and/or blood. Other physiologically-compatible
solutions comprising suitable ionic concentrations may be used to
provide for isotonicity.
[0027] The concentration of salt of the composition may range from
about 0.1% to about 2.0% by weight with respect to the total weight
of the composition, such as from about 0.25% to about 1.0%, from
about 0.5% to about 1.5%, or from about 0.5% to about 1.0% by
weight with respect to the total weight of the composition, e.g.,
about 0.25%, about 0.5%, about 0.75%, or about 1.0% by weight with
respect to the total weight of the composition. Further, for
example, the composition may comprise a salt solution having an
osmolality ranging from about 240 mOsmol/kg to about 340 mOsmol/kg
(e.g., 290 mOsmol/kg.+-.50 mOsmol/kg), such as from about 250
mOsmol/kg to about 320 mOsmol/kg, or from about 280 mOsmol/kg to
about 300 mOsmol/kg. The solution may be physiologically
compatible, e.g., having electrolyte levels, osmolality, and pH
suitable for injection into a patient. The pH of the solution may
be adjusted using a suitable base such as sodium hydroxide to
increase pH and/or a suitable acid such as hydrochloric acid, or
may adjusted by other means or with other substances providing for
a biocompatible composition.
[0028] The composition may comprise one or more other biocompatible
compounds or agents. For example, the composition may comprise a
biocompatible dye or coloring agent, such as brilliant blue (e.g.,
Brilliant Blue FCF, also known as FD&C Blue 1) indigo carmine
(also known as FD&C Blue 2), indigo carmine lake, FD&C Blue
1 lake, and methylene blue (also known as methylthioninium
chloride). For example, the composition may comprise a dye or
colorant to allow for identification of the submucosal tissue plane
upon injection into tissue, e.g., to determine the amount of tissue
to be removed and/or assess the risk of perforation. Any other
suitable types of biocompatible agents may be used, e.g., to adjust
the pH and/or tonicity of the composition as appropriate for
injection into tissue. For example, the composition may comprise
one or more stabilizers and/or preservatives. According to some
aspects, the composition may comprise an additive such as
epinephrine to limit superficial bleeding. The composition may
include one or more additives that improve visualization of
diseased tissue or that have a therapeutic effect. For example, the
additive may be pharmaceutically active, e.g., actively fighting
cancerous cells.
[0029] As mentioned above, the composition may be formulated as a
gel. For example, to prepare the composition, the gelling agent(s)
may be combined with at least one pharmaceutically-acceptable salt
(and optionally one or more other compounds or agents as discussed
above) in an aqueous solution. The resulting mixture may be heated
at a temperature ranging from about 70.degree. C. to about
130.degree. C., such as from about 80.degree. C. to about
125.degree. C., from about 90.degree. C. to about 115.degree. C.,
or from about 95.degree. C. to about 105.degree. C., e.g., a
temperature of about 70.degree. C., about 75.degree. C., about
80.degree. C., about 85.degree. C., about 90.degree. C., about
95.degree. C., about 100.degree. C., about 105.degree. C., about
110.degree. C., about 115.degree. C., about 120.degree. C., about
125.degree. C., or about 130.degree. C. In some examples, a minimum
temperature from about 70.degree. C. to about 85.degree. C. may be
used. In some examples, the mixture may be heated to boiling, e.g.,
a temperature 100.degree. C.
[0030] The composition may be sterilized according to any suitable
method, e.g., autoclaving, gamma irradiation, or via electron beam.
In at least one embodiment, the composition may be heated at a
temperature sufficient for sterilization, e.g., autoclaved at a
temperature of about 121.degree. C. The composition may be
sterilized according to any suitable method, e.g., autoclaving,
gamma irradiation, or via electron beam.
[0031] The mixture may be heated for an amount of time sufficient
to hydrate the gelling agent and allow for formation of the
three-dimensional gel network. With respect to polysaccharides like
gellan gum, it is believed that the polysaccharide molecules may
undergo a coil to double-helix transition with decreasing
temperature, which may lead to gel formation, e.g., depending on
the ionic strength and pH of the solution. For example, gellan gum
coil molecules may form double helices with a reduction in
temperature, and these helices may aggregate to form junction
zones, resulting in gelation. In water, at low ionic strength and
neutral pH, aggregation of the helices may be impeded by
electrostatic repulsion between negatively charged carboxylic
groups on the gellan molecules. The addition of a salt and/or the
reduction in pH may decrease intermolecular repulsion between the
helices, thereby enhancing junction zone formation, and
consequently, the gel strength. The addition of salt therefore may
facilitate physical cross-linking in an aggregation-like process to
form a continuous, three-dimensional gel network. This continuous,
three-dimensional network may provide for a solid or quasi-solid
gel capable of maintaining its three-dimensional form even when
inverted while in an open container.
[0032] In some aspects of the present disclosure, the mixture of
gelling agent(s) and salt solution may be heated for a time ranging
from about 5 minutes to about 90 minutes, from about 10 minutes to
about 60 minutes, from about 15 minutes to about 45 minutes, or
from about 20 minutes to about 30 minutes, e.g., about 15 minutes,
about 20 minutes, about 30 minutes, or about 45 minutes. The
mixture may be heated with constant or intermittent stirring, e.g.,
with a magnetic stirrer or other appropriate mixing equipment.
While heated the composition may form a low viscosity fluid. The
heat then may be removed and the composition allowed to cool. For
example, the composition may be cooled to a temperature 55.degree.
C. or about 50.degree. C. As the composition cools, it may increase
in viscosity and set into a gel.
[0033] In some embodiments, the composition is allowed to cool
without stirring or other agitation. In such cases, the composition
may form a substantially homogeneous gel, e.g., a continuous solid.
Thus, for example, the composition may have a substantially
continuous, three-dimensional, solid or quasi-solid gel network, as
opposed to an agglomerate of gel particles or a colloid mixture. In
some embodiments, the composition may be agitated as it cools,
e.g., by constant or intermittent stirring. In such cases, the
agitation may at least partially disrupt the structure of the gel,
e.g., breaking apart the three-dimensional network to form
individual gel particles or gel fragments. Additionally or
alternatively, the structure of the gel may be at least partially
disrupted after the composition cools, e.g., by stirring, shaking,
and/or transferring the composition between containers.
[0034] Without intending to be bound by theory, it is believed that
the application of various forces (e.g., shear force, compression
force, stress, friction, etc.) may affect the continuity of the
three-dimensional gel network, which in turn may impact its
properties prior to use in medical procedures such as tissue
resection. For example, transferring the composition between
containers prior to injection may lead to shearing of the
three-dimensional structure of the gel when ultimately injected
into a patient. In some cases, this may limit the effectiveness of
the composition, e.g., by limiting the ability of the gel to
separate tissue layers and/or reducing the amount of time the gel
remains within the tissue (e.g., within submucosal tissue) prior to
diffusion or absorption into the tissue. Preparation of the
compositions according to the methods herein may minimize shearing
of the continuous, three-dimensional network of the gel prior to
injection. Thus, the gel may maintain its three-dimensional
structure until the gel is injected through a needle, whereupon the
structure may form fragments of the original continuous,
three-dimensional network. Those gel fragments may have a diameter
corresponding to the diameter of the injection needle, such that
the fragments are as large as possible in-vivo to retain as much of
the three-dimensional structure of the gel as possible. Injection
of these larger-sized particles or fragments is believed to
increase the amount of time the gel remains within the tissue.
[0035] Embodiments of the present disclosure therefore may prevent
or minimize disruption of the continuous, solid gel structure prior
to injection. For example, the composition may be prepared such
that it sets into a continuous, three-dimensional gel network while
the composition is inside a reservoir of a medical device, such as
an injection device. The composition may form a substantially
homogeneous gel solid or quasi-solid in the reservoir without the
need to disrupt the gel structure by transferring between storage
containers. Thus, shear and/or other forces to the gel composition
may be minimized prior to injecting the gel into a patient.
According to some aspects, the composition is not transferred from
the reservoir into any other container prior to injection from the
reservoir to a target site of a patient.
[0036] Reservoirs suitable for the compositions herein may include,
for example, syringes (e.g., a syringe barrel compatible with a
manual or automatic injection system), flexible pouches such as a
plastic bag, and other fluid containers configured for use with a
suitable injection needle. Exemplary materials suitable for the
reservoir include, but are not limited to, cyclic olefin copolymer,
cyclic olefin polymer, polypropylene, polycarbonate, polyvinyl
chloride, and glass.
[0037] The reservoir may be directly coupled to a needle, e.g., via
a Luer adapter or other suitable connection, or may be indirectly
coupled to a needle via a flexible tube, such as a catheter.
Non-limiting examples of needles coupled a reservoir via a flexible
tube include Interject.TM. sclerotherapy needles by Boston
Scientific. The needle may be a hypodermic needle, and may range
from a size of 7 gauge (4.57 mm outer diameter (OD), 3.81 mm inner
diameter (ID)) to 33 gauge (0.18 mm OD, 0.08 mm ID), e.g., a size
of 16 gauge (1.65 mm OD, 1.19 mm ID), 21 gauge (0.82 mm OD, 0.51 mm
ID), 22 gauge (0.72 mm OD, 0.41 mm ID), 23 gauge (0.64 mm OD, 0.33
ID), or 24 gauge (0.57 mm OD, 0.31 mm ID). Exemplary materials for
the needle include, but are not limited to, metals and metal
alloys, such as stainless steel and Nitinol, and polymers. The
distal tip of the needle may be sharpened, and may have a beveled
shape. The proximal end of the needle may include a suitable
fitting/adaptor (e.g., a Luer adapter) for engagement with a
syringe or other reservoir. In some embodiments, the needle may
include an elongated tube or catheter between the needle tip and
the proximal fitting/adapter.
[0038] As discussed above, the composition may be introduced into a
suitable reservoir of a medical device (e.g., an injection device
or an injection system) after heating the composition. For example,
the mixture of gelling agent(s), salt(s), and water may be
introduced into the reservoir after heating the mixture at a
temperature ranging from about 70.degree. C. to about 130.degree.
C., such as a temperature ranging from about 90.degree. C. to about
110.degree. C.
[0039] The composition subsequently may be allowed to cool and
increase in viscosity to set into a homogeneous, solid or
quasi-solid gel while inside the reservoir. In some embodiments,
the composition may be re-heated after its introduction into the
reservoir and subsequently allowed to cool to set into its final
solid or quasi-solid, three-dimensional gel form. For example, the
composition may undergo one or more heating/cooling cycles once
introduced into the reservoir. According to some aspects, for
example, the composition may be heated twice by initially heating
the mixture of gelling agent(s), salt(s), and water (e.g., to
ensure hydration), and then subsequently heating the composition
after introducing the composition into the reservoir from which it
will be injected, allowing it to cool and set into a gel with a
continuous, three-dimensional structure. According to some aspects,
the composition may not be transferred from the reservoir to any
other container prior to injection from the reservoir directly to
the target site of a patient.
[0040] The composition may be sterilized. For example, the
composition may be autoclaved while inside the reservoir by heating
the composition at or to a temperature of about 121.degree. C., and
the composition subsequently be allowed to cool and set into a
homogeneous solid or quasi-solid gel inside the reservoir.
Additionally or alternatively, the composition may be sterilized
via gamma irradiation or by electron beam after its introduction
into the reservoir.
[0041] In some aspects, the composition may be heated as discussed
above and cooled in an initial storage container, such as a vial,
and subsequently transferred into a suitable reservoir from which
the composition may be injected into a patient. In such cases, the
composition may be agitated as it cools in the initial container to
form an agglomeration of smaller gel particles or gel-like fluid.
Additionally or alternatively, the composition may be agitated,
sheared, extruded, or otherwise broken up after cooling and housed
in the storage container. The agglomeration of gel particles or
gel-like fluid may be subsequently mixed with additional liquid
components (e.g., other viscous agents, including viscous forms of
gellan gum) after the gel has set. The composition then may be
transferred from the storage container to a suitable reservoir,
heated, and subsequently allowed to cool to set into a homogeneous
gel inside the reservoir. The composition then may be injected
directly from the reservoir through a needle to the target site of
a patient. According to some aspects, the gel may be subjected to
minimal shear forces and/or other forces prior to injection into a
patient. The viscosity of the composition while set into gel form
within the reservoir, prior to injection, may depend on the
properties of the gelling agent(s) and/or the concentration of the
gelling agent(s) relative to other components of the
composition.
[0042] FIG. 1A illustrates an exemplary syringe 10 providing a
reservoir for a gel composition as discussed above. The syringe 10
may comprise a barrel 12, a plunger 14, and one or more stoppers
16. The composition 15 may be prepared as discussed above and
allowed to set into a solid gel with a continuous,
three-dimensional structure across the diameter of the barrel 12.
The barrel 12 may include a Luer adapter (or other suitable
adapter/connector), e.g., at the distal end 18 of the barrel 12,
for attachment to an injection needle 50 via a flexible catheter
29. The proximal end of the catheter 29 may include a suitable
connection 20 for receiving the barrel 12. In other examples, the
barrel 12 may be directly coupled to the injection needle 50. The
syringe barrel 12 may serve as a reservoir, containing a gel
composition 15 for injection through the needle 50.
[0043] FIG. 1B illustrates an exemplary syringe 30 for use with an
automatic injection system 45. The syringe 30 may include any of
the features of the syringe 10 of FIG. 1A, e.g., a barrel 32, a
plunger 34, and a Luer adapter (or other suitable
adapter/connector) at the distal end 38 of the barrel 32. A
composition 15 may be prepared as discussed above and allowed to
set into a gel in the barrel 32, and the syringe 30 may be inserted
into a channel 47 of the injection system 45 for automatic control
over the amount of gel injected. The distal end 38 of the syringe
30 may be coupled to an injection needle (e.g., similar to
injection needle 50 of FIG. 1A) via a catheter 39. According to
some aspects of the present disclosure, the plunger 34 may form
part of the injection system 45 and the barrel 32 may be a separate
component, e.g., a replaceable cartridge, to be connected to the
injection system 45. For example, the composition 15 may be
prepared in the barrel 32 as a replaceable cartridge having a
proximal attachment compatible with a plunger component of the
injection system 45.
[0044] FIG. 1C illustrates an exemplary reservoir 60 according to
some aspects of the present disclosure. The reservoir 60 may be
provided by a flexible pouch or bag, such as an IV bag. A
composition 15 may be prepared as discussed above and allowed to
set into a gel in the reservoir 60. The reservoir 60 may be
sterile, and may comprise a plastic material such as polyvinyl
chloride (PVC) (e.g., with a plasticizer such as bis(2-ethylhexyl)
phthalate (DEHP)) or a non-PVC plastic material. The pouch may
include a Luer adapter 63 for attachment to a catheter 69 and/or
needle (having any suitable gauge size, as described above) for
injecting the composition 15 into a patient. The reservoir 60 may
be compressible, e.g., to allow for delivery of the composition
through the catheter 69 and/or needle by compression of the
reservoir 60.
[0045] Reservoirs and injection methods other than those
illustrated in FIGS. 1A-1C may be used in according with the
present disclosure. For example, the composition may be housed in a
reservoir coupled to a fluid channel and/or needle that forms part
of an electrocautery device or system. Thus, a physician may inject
the composition through the fluid channel while simultaneously or
subsequently operating other portions of the device or system, such
as an electrocautery knife or snare.
[0046] The amount of force required to move the composition through
a needle aperture (generally described as "peak load" force) may
depend on the viscosity of the composition, the dimensions of the
needle (inner diameter, outer diameter, and/or length), and/or the
material(s) from which the needle is formed. For example, a greater
amount of force may be applied to inject the composition through a
33 gauge needle in comparison to a 7 gauge needle. Additional
factors that may affect the amount of force applied to inject the
composition may include the dimensions of a catheter (inner
diameter, outer diameter, and/or length) connecting the reservoir
to the needle. Suitable peak loads for injection with one or two
hands may range from about 5 lbf to about 25 lbf, such as from
about 10 lbf to about 20 lbf, e.g., about 15 lbf. The loads
measured for a given gel concentration may vary for different
needles and flow rates.
[0047] According to some aspects of the present disclosure, the
size of the needle may be chosen based on the viscosity and/or
components of the composition, or vice versa. Further, the
dimensions of the catheter tubing (inner diameter, outer diameter,
and/or length), if any, may affect the types and amount of force
applied to the composition during injection. These parameters may
be taken into consideration according to the properties of the
composition and the needs of the patient. According to some aspects
of the present disclosure, the size of the needle may be 23 gauge
or 25 gauge. In some cases, a larger size of 20 gauge, 21 gauge, or
22 gauge may be used to inject the compositions herein.
[0048] In some examples, the composition may be pseudoplastic.
Pseudoplasticity generally refers to the property of decreasing in
viscosity upon the application of shear force. Thus, for example,
the composition may have a higher viscosity at rest or under low
shear conditions (e.g., while stored in a container) than while
under high shear conditions (e.g., during loading into and/or
injection through a needle). Examples of materials that may exhibit
pseudoplasticity include gellan gum and xanthan gum, among other
types of polysaccharides.
[0049] The compositions herein may be used in various medical
procedures, including tissue resection procedures of the GI system,
the respiratory system, and/or the genitourinary system. The tissue
resected in such medical procedures may comprise diseased or
injured tissue, non-diseased tissue, or a combination thereof.
Exemplary tissue resection procedures include endoscopic mucosal
resection (EMR) and endoscopic submucosal dissection (ESD). In
these procedures, an endoscope is typically inserted into the
patient's esophagus and advanced through the GI system to reach the
target site in the esophagus, stomach, or intestine. EMR is
typically used for removal of tissue smaller than 2 cm in diameter,
e.g., to biopsy tissue or to remove injured or diseased tissue
(e.g., a cancerous lesion), while ESD is typically used for removal
of larger lesions.
[0050] In some aspects, a continuous solid or quasi-solid gel
composition may be prepared as discussed above and injected between
two layers of tissue, e.g., injected into submucosal tissue between
an upper mucosal layer and lower muscularis propria layer at a
target treatment site. The composition may be injected within the
submucosal space (submucosal layer) under a portion of tissue,
whereupon the injected gel may cause the mucosal tissue to separate
from the muscularis propria layer, elevating the mucosal tissue
layer. A suitable cutting device, e.g., an electrocautery cutting
device such as a knife, snare, scissors, or forceps, may then be
used to remove the portion of tissue. For removal of larger
portions of tissue (e.g., via ESD), the composition may be injected
under the portion of tissue, wherein the gel elevates the upper
layer of tissue from the lower layer. The cutting device then may
be used to make an incision around the portion of tissue and remove
it. The composition may be injected in the submucosal layer to
assist in removing additional portions of tissue.
[0051] In some aspects, the composition may maintain separation of
the tissue layers throughout the entire resection procedure. A
portion of the gel composition may be removed via the resection
process. Following tissue resection, remaining portions of the gel
composition may be flushed from the site with water or saline, or
may naturally diffuse into the tissue.
[0052] FIGS. 2A-2E illustrate an exemplary resection procedure
according to some aspects of the present disclosure. For example,
the procedure may be EMR or ESD as discussed above, or any other
suitable medical procedure for resecting tissue. FIG. 2A shows a
cross-sectional view of two portions of tissue or tissue layers 80,
82, which may be separated by a middle layer 81 of tissue (such as,
e.g., upper mucosal and lower muscularis propria layers separated
by a middle submucosal tissue layer). One or both of the portions
of tissue 80, 82 may include a section of tissue 85 targeted for
removal. For example, the section of tissue 85 may comprise injured
or diseased tissue, or may comprise tissue targeted for biopsy and
subsequent analysis. In the example of FIG. 2A, the section of
tissue 85 is located toward the tissue surface, however, the
devices and compositions disclosed herein may be used to remove
tissue from inner tissue layers.
[0053] As shown in FIG. 2B, an endoscope 100 defining one or more
lumens (e.g., three lumens as shown) may be used to deliver a
needle 70 to the treatment site. The needle 70 may have a hollow
lumen and a sharp, beveled tip 72 for piercing the tissue surface
such that the needle tip 72 is within the middle layer 81 between
the upper and lower portions of tissue 80, 82. The needle lumen may
be in communication with a fluid reservoir, such as a syringe or
other reservoir containing a continuous, solid gel composition 90
prepared as discussed above. The syringe may be used to inject the
composition 90 into the middle layer 81 between the portions of
tissue 80, 82 to form a cushion or bleb of gel, as shown in FIG.
2B. Once the composition 90 is injected, the volume of the gel 90
may cause the upper and lower portions of tissue 80, 82 to
separate, such that the section of tissue 85 may be elevated from
underlying tissue. An electrocautery snare 74 or other cutting
device 74 (such as, e.g., an electrocautery knife, scissors, or
forceps, among other suitable cutting devices) may be used to cut
and remove the section of tissue 85, as shown in FIGS. 2C and 2D.
Once the section of tissue 85 is removed, as shown in FIG. 2E, a
portion of the gel 90 may naturally diffuse into one or more of the
tissue layers 80, 81, 82.
[0054] Other aspects and embodiments of the present disclosure will
be apparent to those skilled in the art from consideration of the
specification and practice of the embodiments disclosed herein.
While certain features of the present disclosure are discussed
within the context of exemplary tissue resection procedures, the
compositions, systems, and methods may be used for other medical
procedures according to the general principles disclosed.
EXAMPLES
[0055] The following examples are intended to illustrate the
present disclosure without, however, being limiting in nature. It
is understood that the present disclosure encompasses additional
aspects and embodiments consistent with the foregoing description
and following examples.
Example 1
[0056] Compositions A-C were prepared according to Table 1 below as
follows. Gellan gum (Gelzan.TM. CM, CP Kelco) and erioglaucine
disodium salt (FD&C Blue 1, Sigma Aldrich) were added to
phosphate buffered saline (PBS) solution and continuously stirred
with a magnetic stirrer and bar. The PBS solution was prepared by
dissolving 1 package PBS powder (Sigma Aldrich) in 1000 ml
deionized water to produce 0.138 M NaCl. The gellan gum/salt/PBS
mixture was brought to a boil with stirring, turning from slightly
cloudy blue to transparent blue in appearance. The solution was
allowed to cool to room temperature (.about.25.degree. C.) with
stirring, resulting in a viscous fluid.
TABLE-US-00001 TABLE 1 Gellan gum Erioglaucine disodium PBS
Composition (% w/w) salt (% w/w) (% w/w) A 0.10 0.004 99.90 B 0.15
0.004 99.85 C 0.20 0.004 99.80
[0057] Each solution was drawn up into a 10-ml syringe (BD Luer-Lok
Tip). Each syringe was autoclaved at 121.degree. C. The syringes
were then allowed to cool to room temperature (.about.25.degree.
C.). The resulting syringe contents comprised a quasi-solid gel
that maintained its shape upon inversion, but that could be
injected through a needle.
[0058] A comparative composition (Composition D) was prepared with
0.20% xanthan gum (Sigma Aldrich), 0.004% erioglaucine disodium
salt (FD&C Blue 1, Sigma Aldrich), and 99.8% phosphate buffered
saline (PBS) solution, and continuously stirred with a magnetic
stirrer and bar. The resulting solution formed a Composition D in
the form of a viscous fluid, rather than a quasi-solid gel as for
gellan gum Compositions A-C. The viscous fluid of the xanthan gum
Composition D was capable of flowing upon inversion.
Example 2
[0059] The syringes containing gellan gum Compositions A-C prepared
according to Example 1 were connected to an injection needle
(Boston Scientific Interject.TM. 23 ga Needle) and injected at 3
mm/s (0.5 ml/s flow rate) using an Instron 5564 Universal Testing
Machine and 500N load cell and custom fixtures. The measured peak
load values were observed to vary based on gellan gum
concentration, as shown in Table 2.
TABLE-US-00002 TABLE 2 Composition Average Peak Load (lbf) A 13.28
B 17.60 C 22.87
[0060] It is intended that the specification and examples be
considered as exemplary only, with a true scope and spirit of the
present disclosure being indicated by the following claims.
* * * * *